Liposome-based formulations are widely used for nucleic acid delivery. Most commercially available lipid or liposome formulations contain at least one positively charged lipid. It has been assumed that the presence of this positively charged lipid is essential for obtaining a high degree of nucleic acid loading and enhancement of liposome fusogenic properties. Several screens have been performed previously to identify optimal positively charged lipid chemistries but all the formulations that have been developed are characterized by the major issues of high levels of toxicity. In fact, in vivo limited therapeutic indexes have been reported for liposome formulations containing positively charged lipids at concentrations only slightly higher than concentrations required to achieve silencing. It would be of great benefit to develop non-toxic delivery vehicles for nucleic acids.